MHC class II compartment subtypes: structure and function

Stern, Lawrence J.; Potolicchio, Ilaria; Santambrogio, Laura

doi:10.1016/j.coi.2005.11.005

Cited by 55 publications

(71 citation statements)

References 47 publications

(41 reference statements)

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“…HLA class II molecules assemble in the endoplasmic reticulum with the Ii and reach the endosomal/lysosomal compartment, where Ii is proteolytically degraded leaving the CLIP fragment in the peptide binding site [14][15][16]. In the endocytic compartments, DM catalyzes the dissociation of CLIP, facilitating peptide loading onto class II molecules [18][19][20].…”

Section: Discussionmentioning

confidence: 99%

“…A large number of antigens and peptides require extensive proteolytic processing in the highly acidic late endocytic vesicles where newly synthesized class II molecules can release CLIP and bind antigenic peptides [14][15][16]. The presentation of such epitopes may be disrupted if the transport of nascent class II molecules is blocked by inhibitors that alter Ii and/or DM functions.…”

Section: Introductionmentioning

confidence: 99%

“…This recycling pathway provides an additional route for peptide binding to class II molecules. HLA class II ab heterodimers are assembled within the endoplasmic reticulum in association with the invariant chain (Ii) [14,15]. Class II dimers are prevented from binding immunogenic epitopes because their binding pocket is occupied by the class II-associated Ii peptide (CLIP) [14][15][16].…”

mentioning

confidence: 99%

“…HLA-DO has been proposed to play an inhibitory role in the antigen presentation process in B cells, because it is thought to form a complex with DM, disrupting DM editing of low-affinity peptides [23][24][25]. Thus, the presence or absence of DM/DO in APC may influence the presentation of autoantigens such as CII.A large number of antigens and peptides require extensive proteolytic processing in the highly acidic late endocytic vesicles where newly synthesized class II molecules can release CLIP and bind antigenic peptides [14][15][16]. The presentation of such epitopes may be disrupted if the transport of nascent class II molecules is blocked by inhibitors that alter Ii and/or DM functions.…”

mentioning

confidence: 99%

“…DM editing was observed with DR4 complexes loaded with the non-glycosylated collagen peptide as well as complexes containing naturally processed epitopes from glycosylated collagen, thus suggesting that complex stability is likely determined by the conserved peptide backbone of these epitopes. Thus, DM-negative APC in inflamed tissues may preferentially present the CII dominant peptide/epitope to T cells regardless of antigen glycosylation, such that even low levels of dominant peptide presentation by class II alleles associated with RA susceptibility may be sufficient for induction of autoimmune disorders.HLA class II molecules assemble in the endoplasmic reticulum with the Ii and reach the endosomal/lysosomal compartment, where Ii is proteolytically degraded leaving the CLIP fragment in the peptide binding site [14][15][16]. In the endocytic compartments, DM catalyzes the dissociation of CLIP, facilitating peptide loading onto class II molecules [18][19][20].…”

mentioning

confidence: 99%

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HLA‐DM negatively regulates HLA‐DR4‐restricted collagen pathogenic peptide presentation and T cell recognition

et al. 2008

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Rheumatoid arthritis, an autoimmune disease, is significantly associated with the HLA class II allele HLA-DR4. While the etiology of rheumatoid arthritis remains unknown, type II collagen (CII) is a candidate autoantigen. An immunodominant pathogenic epitope from this autoantigen, CII [261][262][263][264][265][266][267][268][269][270][271][272][273] , which binds to HLA-DR4 and activates CD4 + T cells, has been identified. The non-classical class II antigen, HLA-DM, is also a key component of class II antigen presentation pathways influencing peptide presentation by HLA-DR molecules expressed on professional antigen-presenting cells (APC). Here, we investigated whether the HLA-DR4-restricted presentation of the pathogenic CII 261-273 epitope was regulated by HLA-DM expression in APC. We show that APC lacking HLA-DM efficiently display the CII [261][262][263][264][265][266][267][268][269][270][271][272][273] peptide/epitope to activate CD4 + T cells, and that presentation of this peptide is modulated dependent on the level of HLA-DM expression in APC. Mechanistic studies demonstrated that the CII [261][262][263][264][265][266][267][268][269][270][271][272][273] peptide is internalized by APC and edited by HLA-DM molecules in the recycling pathway, inhibiting peptide presentation and T cell recognition. These findings suggest that HLA-DM expression in APC controls class IImediated CII [261][262][263][264][265][266][267][268][269][270][271][272][273] peptide/epitope presentation and regulates CD4 + T cell responses to this self epitope, thus potentially influencing CII-dependent autoimmunity.Key words: CD4 + T cells Á HLA-DM Á HLA-DR Á Peptide presentation Á Type II collagen IntroductionType II collagen (CII) is the major protein component of articular cartilage [1]. It is thought that T and B cell responses to this autoantigen are associated with the development and pathogenesis of rheumatoid arthritis (RA) [2,3]. It is also widely believed that RA is genetically linked to HLA class II molecules, including some HLA-DR4 alleles, and that T cell responses in collagendependent RA are directed towards the immunodominant pathogenic epitope CII [261][262][263][264][265][266][267][268][269][270][271][272][273] [4,5]. Studies also suggest that T cells from patients with RA predominantly recognize the glycosylated form of the immunodominant CII peptide [6,7]. Professional antigen-presenting cells (APC) such as B cells, macrophages and dendritic cells abundantly express HLA class II proteins and play critical roles in the pathogenesis of autoimmune arthritis by presenting autoantigens to T cells [4,5,8].In RA, cartilage proteins including CII undergo degradation by proteases, leading to the generation of peptides that can bind to HLA class II proteins and trigger CD4 + T cell activation [9]. Studies suggest that the peptides are loaded onto class II proteins Eur. J. Immunol. 2008. 38: 1961-1970 Immunomodulation in the endosomal and lysosomal compartments of APC prior to transit to the cell surface for T cell recognition [5...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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HLA‐DM negatively regulates HLA‐DR4‐restricted collagen pathogenic peptide presentation and T cell recognition

et al. 2008

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Genome Evolution Studied Through Protein Structure

Bourne

Briedis

Dupont

et al. 2010

Evolutionary Genomics and Systems Biology

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The transferrin receptor and the tetraspanin web molecules CD9, CD81, and CD9P‐1 are differentially sorted into exosomes after TPA treatment of K562 cells

Abache

Naour

Planchon

et al. 2007

J of Cellular Biochemistry

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Here we show that treatment of K562 cells with the phorbol ester TPA induces the down-modulation of various surface antigens. Among them, the transferrin receptor (TfR), the tetraspanin CD81, and a CD81-associated protein, CD9P-1, were unique in that their expression levels were lower after 24 h incubation than after 3 h. We demonstrated that like the TfR, CD81 was internalized at early times, and was less synthesized at latter times. Despite the association of a fraction of the TfR with CD81, these two molecules were subjected to different fates. TPA increased targeting of CD81 and CD9P-1 into exosomes but strongly reduced the localization of the TfR in these vesicles. Using this model we have shown that a fraction of CD81 and CD9P-1 in exosomes comes from a surface pool and that these molecules remain associated in exosomes. However, CD9P-1 could be targeted to exosomes in the absence of CD81 and of another tetraspanin, CD9. The targeting of CD9 into exosomes did not require palmitoylation of the protein. J. Cell. Biochem. 102: 650-664, 2007. (c) 2007 Wiley-Liss, Inc.

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MHC class II compartment subtypes: structure and function

Cited by 55 publications

References 47 publications

HLA‐DM negatively regulates HLA‐DR4‐restricted collagen pathogenic peptide presentation and T cell recognition

HLA‐DM negatively regulates HLA‐DR4‐restricted collagen pathogenic peptide presentation and T cell recognition

Genome Evolution Studied Through Protein Structure

The transferrin receptor and the tetraspanin web molecules CD9, CD81, and CD9P‐1 are differentially sorted into exosomes after TPA treatment of K562 cells

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